The long-term objective of this research program is to develop novel types of phosphoramidate-based anticancer drugs and evaluate their mechanisms of action and toxicity. This drug development program is based upon the design and synthesis of prodrug molecules that exploit unique chemistry for intracellular activation and release of active agents that could otherwise not penetrate the cell. This chemistry is especially well suited to the intracellular release of therapeutically relevant nucleotides and phosphotyrosine peptidomimetics, and the approach provides a strategy for the intracellular delivery of many novel drug candidates. Design and synthesis of prodrugs targeted to the SH2 domain represents a novel and potentially exciting application of this technology. Specific aims to achieve our objectives include: 1) Complete the synthesis and mechanistic evaluation of novel indolequinone phosphoramidates; 2) Design, synthesize and evaluate novel nucleoside phosphoramidate prodrugs; and 3) Design, synthesize and evaluate a series of novel phosphotyrosine peptidomimetic prodrugs. New compounds will be evaluated both in vitro and in vivo using established assays to evaluate potential antitumor activity. New cell-based assays to measure disruption of SH2 domain interactions have been developed and will be applied to the evaluation of phosphotyrosine mimetic prodrugs. Promising candidates will be evaluated in human tumor xenograft models. The ultimate goal is to exploit the unique properties of phosphoramidate chemistry to develop new drugs that exhibit clinical efficacy against resistant or poorly responsive solid tumors.